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      Transport of brain-derived neurotrophic factor across the blood–brain barrier

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      Neuropharmacology
      Elsevier BV

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          Abstract

          Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent for degenerative disorders of the central nervous system. In this report, we investigated the ability of BDNF to cross the blood-brain barrier (BBB). BDNF was stable in blood up to 60 min after i.v. injection, with evidence for aggregation, and had an early, rapid influx into brain. By 10 min, most of the BDNF sequestered by the cerebral cortex was associated with the parenchyma rather than with the endothelial cells, demonstrating complete passage across the BBB. A small dose of unlabeled BDNF enhanced the entry of 125I-BDNF from blood to brain after an i.v. bolus injection, whereas larger doses had no effect. In contrast, a large dose of unlabeled BDNF inhibited the influx of 125I-BDNF during in situ brain perfusion. After intracerebroventricular injection, the efflux of BDNF from brain to blood occurred at a rate similar to that for reabsorption of cerebrospinal fluid, and no evidence for self-inhibition was found. Therefore, we conclude that intact BDNF in the peripheral circulation crosses the BBB by a high-capacity, saturable transport system.

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          Most cited references15

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          BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease

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            Murine tumor necrosis factor alpha is transported from blood to brain in the mouse.

            The cytokines are important components of the brain-immune axis. Recent work has shown that [125I]IL-1 alpha and [125I]IL-1 beta are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNF alpha) labeled with 125I (I-mTNF alpha) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNF alpha showed that this transport system was saturable, and lack of inhibition by IL-1 alpha, IL-1 beta, IL-6, or MIP-1 alpha showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the i.v. injection of I-mTNF alpha showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNF alpha in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNF alpha from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNF alpha is sequestered by the brain. The BBB was not disrupted by up to 50 micrograms kg-1 of mTNF alpha i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Passage of Cytokines across the Blood-Brain Barrier

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                Author and article information

                Journal
                Neuropharmacology
                Neuropharmacology
                Elsevier BV
                00283908
                December 1998
                December 1998
                : 37
                : 12
                : 1553-1561
                Article
                10.1016/S0028-3908(98)00141-5
                3cc63764-3563-41ad-8b12-b7d568d0bc70
                © 1998

                https://www.elsevier.com/tdm/userlicense/1.0/

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